Professor Kefah Mokbel MB, BS, MS, FRCS

Endocrine Therapy

Hormone Therapy – What is it and How is it Used?

There is evidence that the female sex hormone oestrogen stimulates breast cancer to grow and to spread. Consequently, patients are advised to stop using any drugs containing oestrogen, such as the contraceptive pill and HRT, if they develop breast cancer. The use of drugs/treatments that oppose the effect of oestrogen or reduce its production can be useful in estrogen receptor (ER) positive breast cancer treatment. Such drugs/treatments thatare used to manipulate the sex hormones are:

Anti-oestrogens, e.g. tamoxifen, Fulvestrant (Faslodex)

‘Switching off’ of ovaries, e.g. Zoladex

Aromatase inhibitors, e.g. Letrozole, Anastrozole and Exemestane

Tamoxifen

Tamoxifen, also called Nolvadex, acts against oestrogen. The drug has been shown to prolong life and to reduce the risk of cancer recurring in the same breast. It also reduces the possibility of developing cancer in the other breast.

Tamoxifen is particularly effective if the cancer contains special proteins, called oestrogen receptors (ERs, for short). All women with oestrogen receptor-positive breast cancer are, therefore, advised to take tamoxifen for 5-10 years. Other benefits of taking tamoxifen are a decrease in the risk of getting bone fractures due to osteoporosis (brittle bone disease).

What are the Side-effects of Tamoxifen?

One in three patients taking tamoxifen experiences minor side-effects. These include hot flushes, weight gain, dizziness, change in bowel habits, suppression of periods (in young women) and visual disturbances.

Tamoxifen affects the lining of the womb, where it can cause the growth of polyps. It also causes a slight increase in the risk of developing cancer of the womb, of about 1 per 1000 per year. This means that if 1000 women take tamoxifen for one year, one of them will develop womb cancer. Any women taking tamoxifen should consult her doctor if she notices any abnormal vaginal bleeding or discharge.

Tamoxifen also increases the risk of thrombosis (blood clot) and stroke. This risk is very small (of the order of 1 per 1000 per year), but postmenopausal women with a personal or family history of thrombosis or womb cancer should be considered for one of the new drugs: Femara, Arimidex or Aromasin. Early results have demonstrated that these drugs are superior to tamoxifen and are much less likely to cause vein thrombosis or womb cancer.

Faslodex

This anti-estrogen is given by intramascular injection every 4 weeks and used as a second and third line anti-hormonal therapy in postmenopausal women with ER positive breast cancer.

‘Switching off’ the Ovaries

The ovaries are the main source of production of sex hormones such as oestrogen. As mentioned earlier, oestrogen seems to stimulate the growth of breast tumours. Women who have not gone through the menopause will have active ovaries, so removing this source of oestrogen may be desirable, resulting in regression of hormone-receptor-positive breast cancer.

Ovarian function can be ‘switched off’ in three ways:

Surgical removal – this is obviously irreversible and requires a general anaesthetic. The operation can be performed using keyhole surgery techniques and is called laparoscopic oophorectomy.

Drugs – pharmaceutical companies have recently developed special drugs that can reversibly switch off the ovaries, such as goserelin (Zoladex). This drug is given by injection once a month. The side-effects of these drugs include decreased sexual desire, skin rashes, hot flushes, depression and diarrhoea.

Radiation – this method is not commonly used nowadays because of potential side-effects and the development of more effective and safer alternatives.

The switching off of the ovaries with drugs such as goserelin can be used in the treatment of hormone receptor-positive metastatic breast cancer in premenopausal women in combination with tamoxifen or aromatase inhibitors.

Aromatase Inhibitors (AI’s)

In post-menopausal women, the ovaries are no longer functional and cannot produce oestrogen. Their main source of oestrogen comes from the adrenal glands and from special proteins, called enzymes that act on areas of the body such as fatty tissue. One of the most important of these enzymes is called aromatase. A new group of drugs called aromatase inhibitors reduce oestrogen production in post-menopausal women by blocking the action of the aromatase enzymes. Premenopausal women can be rendered postmenopausal with drugs that switch off the ovaries.

Examples of these drugs are letrozole (Femara), anastrozole (Arimidex) and exemestane (Aromasin).

These drugs are prescribed for post-menopausal women with advanced or early breast cancer containing oestrogen receptors (ER positive) . Post-menopausal women with advanced breast cancer or whose breast cancer progresses or relapses while on tamoxifen are also suitable for treatment with this type of drug, provided that the cancer contains oestrogen receptors. These drugs are less likely than tamoxifen to cause weight gain, womb cancer or deep-vein thrombosis.

Studies comparing AI’s with tamoxifen in postmenopausal women with early breast cancer that contains hormone receptors, suggest that these drugs are better than tamoxifen in preventing breast cancer recurrence and have less-frequent side-effects. Futhermore, the use of aromatase inhibitors in sequence after tamoxifen (for 2 years) for early breast cancer in postmenopausal women improves outcome. Women completing 5 years of tamoxifen seem to benefit further if they take AI’s for further 2 to 5 years.

However, bone mineral density scans may be required to identify women at risk of brittle bone disease. In such cases, other drugs to protect the bone can be given in conjunction with aromatase. It is also likely that these drugs may be used to prevent breast cancer in high-risk women.

The author believes that for postmenopausal women diagnosed with low risk (node negative, smaller than 2 cm) early invasive breast cancer that contains hormone receptors, the best approach would be to take tamoxifen for 2 years and then to switch from tamoxifen to an aromatase inhibitor for 3 years. For postmenopausal women diagnosed with high risk (node positive, larger than 2 cm) early invasive breast cancer that contains hormone receptors, the best approach would be to take AI’s for 10 years. For women completing 5 years of tamoxifen, AI’s should be considered for further 5 years especially in node positive patients. Vitamin D supplements and monitoring of bone density are recommended whenever aromatase inhibitors are used.

Biological Therapy to overcome resistance to hormonal therapy

Some breast cancers develop resistance to anti-hormonal therapy therefore certain drugs have been recently developed to overcome this resistance. Such drugs include Everolimus (Afinitor) and Palbociclib (Ibrance). These drugs block certain growth pathways in order to make hormonaltherapy more effective against ER positive breast cancer. They are licensed for use in advanced breast cancer and palbociclib is currently being evaluated for the treatment of early breast cancer. These drugs block two enzymes known as CDK4 and CDK6. These drugs are used in combination with aromatase inhibitors or Faslodex.

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